VA Class:CN105

AHFS Class:

• Selective Serotonin Agonists 28:32.28

Generic Name(s):

• Rizatriptan Benzoate

Chemical Name:

• N , N -Dimethyl-5-(1 H -1,2,4-triazol-1-yl-methyl)-1 H -indole-3-ethanamine monobenzoate

Molecular Formula:

• C₁₅H₁₉N₅•C₇H₆O₂

Rizatriptan benzoate is a selective agonist of serotonin (5-hydroxytryptamine; 5-HT) type 1B and 1D receptors (“triptan”).1,2,3,21

Vascular Headaches

Migraine

Rizatriptan benzoate is used for the acute treatment of attacks of migraine with or without aura in adults and pediatric patients 6-17 years of age.1 The manufacturer states that rizatriptan should not be used for the management of hemiplegic or basilar migraine or for the prophylaxis of migraine.1 Safety and efficacy have not been established for the management of cluster headaches.1

The current indication for rizatriptan in adults is based principally on the results of 4 randomized, placebo-controlled studies of rizatriptan conventional tablets4,5,6,7 and 2 similarly designed studies of rizatriptan orally disintegrating tablets1,8 in adults with moderate to severe headaches.1,9 In these studies, substantially more patients receiving single doses of rizatriptan 5 or 10 mg achieved a response (mild or no headache pain) 2 hours after treatment compared with patients receiving placebo.1,4,5,6,6,7,8 Rizatriptan also relieved manifestations of migraine other than headache (including nausea, photophobia, and phonophobia),1,4,5,6,6,7,8 reduced the need for supplemental migraine therapy,1,4,5,6,6,8 and improved functional ability.1,4,5,6,6,7,8 Limited data from studies of up to one year's duration suggest that intermittent rizatriptan has remained effective throughout subsequent migraine attacks.4,10 Data from several comparative studies indicate that rizatriptan is at least as effective as oral sumatriptan in alleviating the pain associated with migraine 2 hours after treatment.3,5,7,11

Efficacy of rizatriptan in pediatric patients has been established in a randomized double-blind, placebo-controlled study of the orally disintegrating tablets in pediatric patients 6-17 years of age (mean age: 13 years) with moderate to severe migraine headaches.1,24 Patients enrolled in the study had at least a 6-month history of migraine attacks with or without aura and an inadequate response to nonsteroidal anti-inflammatory agents (NSAIAs) and acetaminophen.1,24 In this study, substantially more patients receiving rizatriptan (5 mg in those weighing at least 20 kg but less than 40 kg and 10 mg in those weighing 40 kg or more) achieved a response (no headache pain) 2 hours after treatment compared with patients receiving placebo;1,24 however, the frequency of migraine-associated symptoms (i.e., nausea, photophobia, phonophobia) at 2 hours after treatment was similar in those receiving rizatriptan and those receiving placebo.1

The US Headache Consortium considers 5-HT_1B/1D receptor agonists (e.g., rizatriptan) an appropriate treatment choice for the acute management of moderate to severe migraine headaches in patients without contraindications to these drugs and recommends use of 5-HT_1B/1D receptor agonists, dihydroergotamine, or ergotamine in patients with more severe migraine attacks as well as in patients in whom previous therapy with nonsteroidal anti-inflammatory agents or fixed-combination preparations such as acetaminophen, aspirin, and caffeine has been ineffective.12,13 For further information on management and classification of migraine headache, see Vascular Headaches: General Principles in Migraine Therapy, under Uses in Sumatriptan 28:32.28.

Rizatriptan benzoate is administered orally without regard to meals.1

The rizatriptan orally disintegrating tablet is packaged in a blister in an aluminum pouch.1 The blister should not be removed from the aluminum pouch until just prior to administration.1 With dry hands, the blister package should be peeled open and the tablet placed on the tongue to dissolve and be swallowed with saliva.1 Administration with liquid is not necessary.1

Dosage

Dosage of rizatriptan benzoate is expressed in terms of rizatriptan.1

Vascular Headaches

Adult Dosage

For the acute treatment of migraine attacks with or without aura in adults, the recommended initial oral dose of rizatriptan is a single dose of 5 or 10 mg.1 Single oral doses of 5 or 10 mg (conventional tablets or orally disintegrating tablets) were effective in clinical studies, although the 10-mg dose may provide a greater effect than the 5-mg dose.1 However, the 10-mg dose also may be associated with an increased risk of adverse effects.1

Although efficacy of a second dose or subsequent doses has not been established in placebo-controlled trials, if the migraine headache recurs, a second dose of rizatriptan may be administered 2 hours after the first dose.1 The maximum dosage administered in any 24-hour period should not exceed 30 mg.1 The safety of treating an average of more than 4 headaches per 30-day period has not been established.1

Pediatric Dosage

For the acute treatment of migraine attacks with or without aura in pediatric patients 6-17 years of age, the recommended dose of rizatriptan is a single dose of 5 mg in patients weighing less than 40 kg or 10 mg in those weighing 40 kg or more.1 Efficacy and safety of more than one dose within any 24-hour period have not been established in pediatric patients.1

Special Populations

Dosage selection for geriatric patients should be cautious, usually starting at the low end of the dosage range, and reflect the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in such patients.1

Contraindications

Ischemic heart disease (e.g., angina pectoris, history of myocardial infarction, documented silent ischemia), coronary artery vasospasm (e.g., Prinzmetal variant angina), uncontrolled hypertension, or other serious underlying cardiovascular disease.1 History of stroke or transient ischemic attack, peripheral vascular disease, or ischemic bowel disease.1 Basilar or hemiplegic migraine.1 Treatment within the previous 24 hours with another 5-HT₁ receptor agonist or with an ergot alkaloid (e.g., ergotamine, dihydroergotamine, methysergide [no longer commercially available in the US]).1 Concurrent or recent (within 2 weeks) treatment with a monoamine oxidase-A (MAO-A) inhibitor.1 Known hypersensitivity to rizatriptan or any ingredient in the formulation.1

Warnings/Precautions

Careful Diagnosis of Migraine

Rizatriptan should be used only in patients in whom a clear diagnosis of migraine has been established.1 If the first attack of migraine treated with rizatriptan fails to respond to the drug, the diagnosis of migraine should be reconsidered before rizatriptan is administered to treat subsequent attacks.1 Care should be taken to exclude other potentially serious neurologic disorders before rizatriptan is administered to patients not previously diagnosed with migraine or to patients who present with atypical symptoms.1

Cardiac Effects

Serious cardiac events, including acute myocardial infarction and fatal or life-threatening cardiac rhythm disturbances (e.g., ventricular tachycardia or fibrillation), have occurred within a few hours following administration of 5-HT₁ receptor agonists.1 Myocardial ischemia/infarction or coronary vasospasm (e.g., Prinzmetal variant angina) may occur even in patients without a history of coronary artery disease.1 Use of rizatriptan is contraindicated in patients with ischemic or vasospastic heart disease.1 (See Cautions: Contraindications.) The drug should be discontinued if disturbances in cardiac rhythm occur.1

Although sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck, and jaw occur frequently following administration of 5-HT₁ receptor agonists, these sensations usually are noncardiac in origin.1 The manufacturer states that a cardiovascular evaluation should be performed if a cardiac origin is suspected.1

Patients with multiple cardiovascular risk factors (e.g., postmenopausal women; men older than 40 years of a patients with risk factors such as hypertension, hypercholesterolemia, smoking, obesity, diabetes, or family history of coronary artery disease) who have not previously received therapy with a 5-HT₁ receptor agonist should undergo cardiovascular evaluation prior to initiation of 5-HT₁ receptor agonist therapy.1 If the evaluation provides evidence of coronary artery disease or coronary artery vasospasm, the drug should not be administered.1 For patients with a satisfactory cardiovascular evaluation, the manufacturer states that consideration should be given to administration of the first dose in a medically supervised setting with electrocardiographic monitoring performed immediately following administration of the dose.1 Periodic cardiovascular evaluation is recommended for patients with risk factors for coronary artery disease who are receiving intermittent long-term therapy with 5-HT₁ receptor agonists.1

For further information on the systematic approach to administering 5-HT₁ receptor agonists in patients with risk factors for the development of coronary artery disease, see Cautions: Precautions and Contraindications, in Sumatriptan 28:32.28.

Cerebrovascular Effects

Cerebral or subarachnoid hemorrhage and stroke, sometimes fatal, have occurred in patients receiving 5-HT₁ receptor agonists.1 In a number of cases, it appears possible that the cerebrovascular event was the primary event, and the 5-HT₁ receptor agonist was administered in the mistaken belief that the patient's symptoms were caused by a migraine attack.1 Patients with migraine may be at increased risk for certain cerebrovascular events (e.g., stroke, hemorrhage, transient ischemic attack).1 Rizatriptan should be discontinued in patients experiencing a cerebrovascular event.1 (See Cautions: Contraindications.)

Other Cardiovascular or Vasospastic Effects

Noncoronary vasospastic reactions, including peripheral vascular ischemia, GI ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud's syndrome, have been reported in patients receiving 5-HT₁ receptor agonists, including rizatriptan.1 (See Cautions: Contraindications.) Transient or permanent blindness and partial vision loss also have been reported in patients receiving 5-HT₁ receptor agonists, although visual disorders may occur as manifestations of migraine attacks.1 Patients experiencing signs or symptoms suggestive of vasospastic reactions following administration of any 5-HT₁ receptor agonist should be evaluated to rule out vasospastic reactions before receiving additional doses of rizatriptan.1

Substantial increases in blood pressure, including hypertensive crisis with acute impairment of organ systems, have been reported rarely following administration of 5-HT₁ receptor agonists in patients with or without a history of hypertension.1 (See Cautions: Contraindications.) In young, otherwise healthy, adult patients who received the maximum recommended rizatriptan dosage (10 mg every 2 hours for 3 doses), slight increases in blood pressure of approximately 2-3 mm Hg were observed.1

Serotonin Syndrome

Potentially life-threatening serotonin syndrome has been reported in patients receiving 5-HT₁ receptor agonists, particularly in those receiving concomitant therapy with selective serotonin-reuptake inhibitors (SSRIs) or selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs).1,20 Serotonin syndrome also may occur in patients receiving 5-HT₁ receptor agonists concomitantly with MAO inhibitors or tricyclic antidepressants.1 Symptoms of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).1,20 If concurrent therapy with a 5-HT₁ receptor agonist and an SSRI or SNRI is clinically warranted, the patient should be observed carefully, particularly during initiation of therapy, when dosage is increased, or when another serotonergic agent is initiated.20 If manifestations of serotonin syndrome occur, treatment with rizatriptan and any concurrently administered serotonergic agents should be discontinued and supportive and symptomatic treatment should be initiated.1,33

Medication Overuse Headache

Excessive use of drugs indicated for the management of acute migraine attacks (e.g., use of 5-HT₁ receptor agonists, ergotamine, opiates, or certain analgesic combinations on a regular basis for 10 or more days per month) may result in migraine-like daily headaches or a marked increase in the frequency of migraine attacks.1,31,32 Detoxification, including withdrawal of the overused drugs; treatment of withdrawal symptoms (which often include transient worsening of headaches); and consideration of prophylactic therapy for migraine attacks may be necessary.1,31,32

Sensitivity Reactions

Hypersensitivity reactions (e.g., angioedema, anaphylaxis, wheezing, toxic epidermal necrolysis) have been reported in patients receiving rizatriptan.1

Phenylketonuria

Individuals who must restrict their intake of phenylalanine should be warned that each 5- or 10-mg Maxalt-MLT^® orally disintegrating tablet contains aspartame, which is metabolized in the GI tract to provide 1.1 or 2.1 mg of phenylalanine, respectively, following oral administration.1 Maxalt^® conventional tablets do not contain aspartame.1

Generic preparations of rizatriptan also may contain aspartame; the manufacturer's prescribing information should be consulted.

Specific Populations

Pregnancy

Category C.1 (See Users Guide.)

The manufacturer has established a pregnancy registry to facilitate assessment of fetal outcomes in women who received rizatriptan during pregnancy.1 Clinicians are encouraged to report prenatal exposures to rizatriptan by calling 800-986-8999.1

Lactation

Rizatriptan is distributed into milk in rats.1 Caution is advised if used in nursing women.1

Pediatric Use

Safety and efficacy have not been established in children younger than 6 years of age.1 Adverse effects in pediatric patients are expected to be similar to those reported in adults.1

Geriatric Use

Pharmacokinetic profile is similar to that in younger adults.1 Clinical studies of rizatriptan did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently than younger patients.1 While other clinical experience has not revealed age-related differences in response, dosage should be selected with caution in geriatric patients.1

Renal Impairment

Exposure to rizatriptan is increased approximately 44% in patients undergoing hemodialysis.1

Hepatic Impairment

Plasma concentrations of rizatriptan are increased approximately 30% in patients with moderate hepatic impairment.1 Rizatriptan has not been studied in patients with severe hepatic impairment.17

Common Adverse Effects

Adverse effects occurring in 2% or more of adults receiving rizatriptan and occurring more frequently with rizatriptan than with placebo include pain/pressure sensations (i.e., chest pain [tightness/pressure, heaviness], pain/tightness/pressure in neck/throat/jaw, regional pain [tightness/pressure/heaviness], pain at location not specified),1 asthenia/fatigue,1,4 dizziness,1,4 headache,1 somnolence,1,4 dry mouth,1,4 nausea,1,4 and paresthesia.1,4

Ergot Alkaloids and Other 5-HT1 Receptor Agonists

Potential pharmacologic interaction (additive vasospastic effects) when rizatriptan is used concomitantly with ergot alkaloids (e.g., ergotamine, dihydroergotamine, methysergide [no longer commercially available in the US]) and other 5-HT₁ receptor agonists.1 Use within 24 hours is contraindicated.1

Monoamine Oxidase (MAO) Inhibitors

Potential pharmacokinetic interaction (increased systemic exposure to rizatriptan and active N -monodesmethyl metabolite) with MAO-A inhibitors.1,16 (See Description.) Use within 2 weeks of MAO-A inhibitor therapy is contraindicated.1

Metoprolol and Nadolol

Pharmacokinetic interaction is unlikely; no dosage adjustment is necessary.1,22

Oral Contraceptives

Pharmacokinetic interaction is unlikely.1,23

Propranolol

Potential pharmacokinetic interaction (increased plasma concentrations of rizatriptan).1,22 When rizatriptan and propranolol are used concomitantly in adults, the maximum recommended rizatriptan dosage is 5 mg per single dose and 3 doses (maximum total dosage of 15 mg) per 24-hour period.1,22 Pediatric patients who weigh 40 kg or more may receive a single 5-mg dose of rizatriptan concomitantly with propranolol; only one 5-mg dose should be administered in any 24-hour period.1 Rizatriptan and propranolol should not be used concomitantly in pediatric patients who weigh less than 40 kg.1

Selective Serotonin-reuptake Inhibitors and Selective Serotonin- and Norepinephrine-reuptake Inhibitors

Potential pharmacologic interaction (potentially life-threatening serotonin syndrome).1,20 If concomitant use is clinically warranted, the patient should be observed carefully, particularly during treatment initiation, when dosage is increased, or when another serotonergic agent is initiated.20 (See Serotonin Syndrome under Cautions: Warnings/Precautions.)

A study in healthy individuals showed no effect of paroxetine on rizatriptan's safety profile or plasma concentrations of rizatriptan and its active N -monodesmethyl metabolite.1,15

Pharmacokinetics

Absorption

Bioavailability

Rizatriptan is completely absorbed from GI tract, 1,2 but absolute bioavailability (as conventional tablet) is 45%,1 indicating first-pass metabolism.1,2 Bioavailability is similar for orally disintegrating tablets.1

Peak plasma concentrations are attained within 1-1.5 hours after administration as conventional tablets; peak concentrations are delayed by up to 0.7 hour when administered as orally disintegrating tablets.1

AUC and peak plasma concentration are approximately 30 and 11% higher, respectively, in females than in males.1

Exposure in pediatric patients 6-17 years of age receiving a single dose at recommended dosage levels is similar to that in adults receiving a single 10-mg dose.1

Food

Food does not substantially affect bioavailability but may delay time to peak concentration by 1 hour.1

Distribution

Extent

Rizatriptan crosses the placenta and is distributed into milk in animals; there are no studies in pregnant or nursing women.1

Plasma Protein Binding

14%.1

Elimination

Metabolism

Rizatriptan is metabolized principally via oxidative deamination by MAO-A to an inactive indole acetic acid metabolite.1 Other minor metabolites, including an N -monodesmethyl derivative with similar activity to the parent compound, have been identified.1

Elimination Route

Rizatriptan is excreted principally in urine (14% of dose as unchanged drug, 51% as indole acetic acid metabolite).1,19

Half-life

Approximately 2-3 hours.1

Special Populations

In patients with moderate hepatic impairment, plasma rizatriptan concentrations are approximately 30% higher than in healthy individuals.1

In hemodialysis patients, AUC is approximately 44% greater than in patients with normal renal function.1 AUC in patients with creatinine clearance of 10-60 mL/minute per 1.73 m² is similar to that in healthy individuals.1

Pharmacokinetic profile in healthy geriatric individuals is similar to that in younger adults.1

Description

Rizatriptan benzoate is a selective agonist of serotonin (5-hydroxytryptamine; 5-HT) type 1B and 1D receptors.1,2,3,21 Rizatriptan is structurally and pharmacologically related to other selective 5-HT_1B/1D receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, sumatriptan, zolmitriptan).1,2,21 Because the mechanisms involved in the pathogenesis of migraine are not clearly understood, the precise mechanism of 5-HT₁ receptor agonists in the management of migraine has yet to be established.1,2,3 However, current data suggest that 5-HT₁ receptor agonists, including rizatriptan, may ameliorate migraine through selective constriction of certain intracranial blood vessels, inhibition of neuropeptide release, and reduced transmission in the trigeminal pain pathway.1,2,21

Rizatriptan is metabolized principally via oxidative deamination by monoamine oxidase-A (MAO-A) to an inactive indole acetic acid metabolite.1 Other minor metabolites, including an N-monodesmethyl derivative with 5-HT_1B/1D receptor activity similar to that of rizatriptan, have been identified.1 Rizatriptan is eliminated principally in urine, with approximately 14% of an administered dose excreted as unchanged drug and 51% as the indole acetic acid metabolite.1

Advice to Patients

Risk of dizziness or somnolence; importance of exercising caution when driving or operating machinery.1

Risk of serious cardiovascular or cerebrovascular events (e.g., myocardial infarction, stroke) or other vasospastic reactions.1 Importance of seeking medical care if symptoms of such reactions (e.g., shortness of breath, weakness, slurring of speech, sudden or severe abdominal pain, difficulty in seeing, or tightness, pain, pressure or heaviness in the chest, throat, neck, or jaw) occur after taking rizatriptan and of not taking rizatriptan again until evaluated by a clinician.1

Importance of adhering to prescribed directions for use.1 Provide copy of manufacturer's patient information.1

For patients taking rizatriptan orally disintegrating tablets, importance of not removing the blister from the outer pouch until just before administering dose; importance of opening blister pack with dry hands and of placing tablet on tongue to dissolve and be swallowed with saliva.1

Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses (e.g., cardiovascular disease).1

Importance of informing patients of risk of serotonin syndrome, particularly with concurrent use of rizatriptan and a selective serotonin-reuptake inhibitor (SSRI) or selective serotonin- and norepinephrine-reuptake inhibitor (SNRI).1,20 Importance of seeking immediate medical attention if symptoms of serotonin syndrome develop.1,21

Overuse of drugs indicated for the management of acute migraine attacks may exacerbate headaches; importance of recording headache frequency and drug use to monitor effectiveness of treatment.1,31

Importance of informing patients with phenylketonuria that rizatriptan orally disintegrating tablets contain aspartame.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Merck and Co., Inc. Maxalt^® (rizatriptan benzoate) tablets and Maxalt-MLT^® (rizatriptan benzoate) orally disintegrating tablets prescribing information. Whitehouse Station, NJ; 2013 Jan.

2. Goadsby PJ, Hargreaves RJ. Mechanisms of action of serotonin 5-HT_1B/1D agonists: insights into migraine pathophysiology using rizatriptan. Neurology . 2000; 55(Suppl 2):S8-S14. [PubMed 11089513]

3. Dooley M, Faulds D. Rizatriptan: a review of its efficacy in the management of migraine. Drugs . 1999; 58:699-723. [PubMed 10551439]

4. Kramer MS, Matzura-Wolfe D, Polis A et al. A placebo-controlled crossover study of rizatriptan in the treatment of multiple migraine attacks. Neurology . 1998; 51:773-81. [PubMed 9748025]

5. Tfelt-Hansen P, Teall J, Rodriguez F et al. Oral rizatriptan versus oral sumatriptan: a direct comparative study in the acute treatment of migraine. Headache . 1998; 38:748-55. [PubMed 11284463]

6. Teall J, Tuchman M, Cutler N et al. Rizatriptan (Maxalt) for the acute treatment of migraine and migraine recurrence. Headache . 1998; 38:281-7. [PubMed 9595867]

7. Lines C, Visser WH, Vandormael K et al. Rizatriptan 5 mg versus sumatriptan 50 mg in the acute treatment of migraine. Headache . 1997; 37:319-20.

8. Ahrens SP, Farmer MV, Williams DL et al. Efficacy and safety of rizatriptan wafer for the acute treatment of migraine. Cephalagia . 1999; 19:525-30.

9. Dahlof CGH, Rapoport AM, Sheftell FD et al. Rizatriptan in the treatment of migraine. Clin Ther . 1999; 21:1823-6. [PubMed 10890255]

10. Block GA, Goldstein J, Polis A et al. Efficacy and safety of rizatriptan versus standard care during long-term treatment for migraine. Headache . 1998; 38:764-71. [PubMed 11284464]

11. Goldstein J, Ryan R, Jiang K et al. Crossover comparison of rizatriptan 5 mg and 10 mg versus sumatriptan 25 and 50 mg in migraine. Headache . 1998; 38:737-47. [PubMed 11284462]

12. Matchar DB, Young WB, Rosenberg JH et al. Evidence-based guidelines for migraine headache in the primary care setting: pharmacological management of acute attacks. From American Academy of Neurology web site. [Web]

13. Silberstein SD, for the US Headache Consortium. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): report of the quality standards subcommittee of the American Academy of Neurology. Neurology . 2000; 55:754-63. [PubMed 10993991]

15. Goldberg MR, Lowry RC, Musson DG et al. Lack of pharmacokinetic and pharmacodynamic interaction between rizatriptan and paroxetine. J Clin Pharmacol . 1999; 39:192-99. [PubMed 11563413]

16. van Haarst AD, van Gerven JMA, Cohen AF et al. The effects of moclobemide on the pharmacokinetics of the 5-HT_1B/1D agonist rizatriptan in healthy volunteers. Br J Clin Pharmacol . 1999; 48:190-6. [PubMedCentral] [PubMed 10417495]

17. Merck, West Point, PA: Personal communication.

19. Vyas KP, Halpin RA, Geer LA et al. Disposition and pharmacokinetics of the antimigraine drug, rizatriptan, in humans. Drug Metab Dispos . 2000; 28:89-95. [PubMed 10611145]

20. Food and Drug Administration. Public health advisory: combined use of 5-hydroxytryptamine receptor agonists (triptans), selective serotonin reuptake inhibitors (SSRIs) or selective serotonin/norepinephirne reuptake inhibitors (SNRIs) may result in life-threatening serotonin syndrome. Rockville, MD; 2006 Jul 19. From the FDA website: ([Web], [Web], and [Web]).

21. Tfelt-Hansen P, De Vries P, Saxena PR. Triptans in migraine: a comparative review of pharmacology, pharmacokinetics and efficacy. Drugs . 2000; 60:1259-87. [PubMed 11152011]

22. Goldberg MR, Sciberras D, De Smet M et al. Influence of beta-adrenoceptor antgaonists on the pharmacokinetics of rizatriptan, a 5HT1B/1D agonist: differential effects of propranolol, nadolol and metoprolol. Br J Clin Pharmacol . 2001; 52:69-76. [PubMedCentral][PubMed 11453892]

23. Shadle CR, Liu G, Goldberg MR. A double-blind, placebo-controlled evaluation of the effect of oral doses of rizatriptan 10 mg on oral contraceptive pharmacokinetics in healthy female volunteers. J Clin Pharmacol . 2000; 40:309-15. [PubMed 10709161]

24. Ho TW, Pearlman E, Lewis D et al. Efficacy and tolerability of rizatriptan in pediatric migraineurs: results from a randomized, double-blind, placebo-controlled trial using a novel adaptive enrichment design. Cephalalgia . 2012; 32:750-65. [PubMed 22711898]

31. Tepper SJ, Tepper DE. Breaking the cycle of medication overuse headache. Cleve Clin J Med . 2010; 77:236-42. [PubMed 20360117]

32. Negro A, Martelletti P. Chronic migraine plus medication overuse headache: two entities or not?. J Headache Pain . 2011; 12:593-601. [PubMedCentral][PubMed 21938457]

33. Bijl D. The serotonin syndrome. Neth J Med . 2004; 62:309-13. [PubMed 15635814]